Schubert Alexis, Grimm Stefan
Max-Planck-Institute for Biochemistry, Martinsried, Germany.
Cancer Res. 2004 Jan 1;64(1):85-93. doi: 10.1158/0008-5472.can-03-0476.
The permeability transition (PT)-pore is an important proapoptotic protein complex in mitochondria. Although it is activated by many signals for apoptosis induction, the role of its various subunits in cell death induction has remained largely unknown. We found that of its components, only the voltage-dependent anion channel in the outer mitochondrial membrane and the adenine nucleotide translocator-1 (ANT-1), a PT-pore subunit of the inner membrane, are apoptosis inducers. We also report that ANT-1's direct interactor, cyclophilin D, can specifically repress ANT-1-induced apoptosis. In addition, cotransfection experiments revealed that for a diverse range of apoptosis inducers, cyclophilin D shows the same repression profile as the compound bongkrekic acid, a specific inhibitor of the PT-pore. This activity seems to be independent of its chaperone activity, the only known function of cyclophilin D to date. Importantly, cyclophilin D is specifically up-regulated in human tumors of the breast, ovary, and uterus, suggesting that inhibition of the PT-pore via up-regulation of cyclophilin D plays a role in tumorigenesis.
通透性转换（PT）孔是线粒体中一种重要的促凋亡蛋白复合物。尽管它可被多种诱导凋亡的信号激活，但其各个亚基在诱导细胞死亡中的作用仍 largely 未知。我们发现，在其组成成分中，只有线粒体外膜上的电压依赖性阴离子通道和内膜的 PT 孔亚基腺嘌呤核苷酸转位酶 1（ANT - 1）是凋亡诱导剂。我们还报告称，ANT - 1 的直接相互作用分子亲环素 D 可特异性抑制 ANT - 1 诱导的凋亡。此外，共转染实验表明，对于多种凋亡诱导剂，亲环素 D 显示出与 PT 孔特异性抑制剂硼酸的相同抑制谱。这种活性似乎独立于其伴侣活性，而伴侣活性是亲环素 D 迄今为止唯一已知的功能。重要的是，亲环素 D 在人类乳腺癌、卵巢癌和子宫肿瘤中特异性上调，这表明通过上调亲环素 D 来抑制 PT 孔在肿瘤发生中起作用。
